Sarepta DMD Candidates Fail to Hit Primary Endpoint in Phase III Confirmatory Trial

CAMBRIDGE, MA —November 4, 2025 —Sarepta Therapeutics is facing a significant setback after announcing that two of its approved Duchenne muscular dystrophy (DMD) therapies, AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen), failed to meet the primary endpoint in the Phase III confirmatory ESSENCE study. The trial, which ran for nine years, was intended to secure full, traditional approval for the therapies, which currently hold Accelerated Approval status from the U.S. Food and Drug Administration (FDA).

The primary endpoint measured functional benefit after 96 weeks, comparing the therapies to a placebo. The study achieved only a 0.05 steps/second difference in least square means (LSM) between the treatment groups and placebo, failing to reach statistical significance.

Clinically Meaningful Trend Despite Statistical Failure

Sarepta suggested the final data was “confounded” by the Covid-19 pandemic. When factoring this into consideration, the treatment still showed a numerical trend favoring the therapies, demonstrating a 30% reduction in decline (LSM 0.11 steps/second). Although this revised figure also lacked statistical significance, Sarepta categorized it as a “clinically meaningful change.” “While the ESSENCE study did not meet statistical significance on its primary endpoint, we believe the results demonstrated a clear treatment effect, showing clinically meaningful functional outcomes for people with Duchenne who have mutations amenable to skipping exons 45 or 53,” said Dr. Louise Rodino-Klapac, Sarepta R&D and technical operations president.

Dr. Rodino-Klapac added that these findings reinforce the potential of the therapies to slow muscle weakness and are consistent with growing real-world evidence.

Intention to Seek Traditional Approval

Despite the ESSENCE trial’s primary endpoint failure, Sarepta announced its intent to move forward. The company plans to schedule a meeting with the FDA to discuss converting AMONDYS 45 and VYONDYS 53 from Accelerated to traditional approval. This discussion will be backed by the ESSENCE data, existing real-world evidence, and the positive safety profile observed during the trial.

The confirmatory trial enrolled 225 patients aged between six and 13 years with DMD mutations amenable to exon 45 or 53 skipping. The study reported no new safety signals, with adverse events (AEs) remaining mostly mild or moderate.